Process for manufacturing chewable dosage forms for drug delivery and products thereof

ABSTRACT

A palatable, soft chewable medication vehicle for delivery of a pharmaceutically acceptable active ingredient, such as a drug, to an animal or human subject. The soft chews contain only food grade or better inactive ingredients, and preferably do not contain ingredients of animal origin. Processes for manufacturing the soft chews do not require the generation of heat during mixing of active and inactive ingredients, provide stable concentrations of the active ingredient, and produce chews of consistent weight and texture.

FIELD OF THE INVENTION

The invention relates to the field of orally administrablepharmaceutical dosage units; in particular, units in the form of anedible mass, such as a chunk.

BACKGROUND OF THE INVENTION

Formulation of a drug into an edible medication, such as a chewabletablet or confection, can increase patient acceptance of the medication,especially animals, who tend to resist swallowing hard tablets orcapsules. Unfortunately, many drugs and other active ingredients(collectively, “actives”) have a strongly bitter or otherwiseunpalatable taste, making chewing them unpleasant.

Flavorings are commonly added to chewable medications to enhance theirpalatability. For example, a veterinary medication might include animalproduct-based flavorings such as uncooked dried meat parts such as beef,pork, chicken, turkey, fish and lamb; organ meats such as liver; meatmeals, bone meals and ground bone; and animal-derived food such ascasein, milk (which may include dry forms and lowered fat forms, such asdry skim milk), yogurt, gelatin, cheese and egg (collectively, “animalorigin flavorings”) may be utilized.

However, use of many animal origin flavorings (especially of meat,poultry or seafood origin) risks exposure to infectious agents, not onlyto the recipient of the drug, but also through contamination ofmanufacturing equipment on which the flavored dosage units are made. Forthis reason, manufacturing facilities that prepare pharmaceuticalproducts with animal origin flavorings are often devoted exclusively totheir preparation, at a correspondingly greater cost than would beincurred if manufacturing could be performed in a facility capable ofconcurrently processing multiple products.

Texture is also an issue for chewable medications. One of the mostcommonly used form for chewable dosage units is the compressed tablet,whose ingredients (including the actives and inactive ingredients suchas binders) can make the tablet gritty or otherwise unappealing,especially to animals. Thus, a preferred alternative dosage form for useespecially with animals is the “soft chew,” generally a meat-like massor chunk also widely found in consumable pet treats.

Soft chews are typically manufactured by blending and extrusion.Pre-mixed ingredients are introduced into an extruder barrel with ascrew therein, then mixed, coagulated, expanded and sheared into ablended mixture, followed by application of additional heat if a hardertexture is desired. Water introduced into the mixture must generally beof pharmaceutical grade, as it will be retained within the mixture. Theblended mixture is then formed into a desired shape on a die plate, thencut into individual units.

The heat generated during the extrusion process can cause deteriorationin the stability (potency or integrity) of the active in the mixture,causing the effective dose provided by each unit formed to vary.Consistency of texture, shape and weights of the chews from batch tobatch of extruded material can also suffer.

There is a need, therefore, for a method of manufacture for softchewable medications in which the blending of actives into the chewmixture is achieved without generation of heat. It is also desirablethat the chews be susceptible to manufacture without use of costly,pharmaceutical grade water as an ingredient. There is also a need in theart for a soft chew medication whose taste appeals to animals withoutuse of ingredients that may include infectious agents or contaminants.Further, it is highly desirable for the manufacturing means employed toproduce chewable medications to do so in a manner that ensuresconsistent chew weights, texture and active dosages.

SUMMARY OF THE INVENTION

The invention provides a unique soft chew medication and processes forits manufacture. The soft chews of the invention are particularlypalatable to pet animals. They contain inactive ingredients of at leastfood grade quality, and most preferably do not contain inactiveingredients of animal origin. As such, the soft chews may bemanufactured without concern about transmission of infectious agents orcontaminants, and without risk of cross-contaminating other productsproduced in the same manufacturing facility.

The manufacturing processes of the invention allow the soft chews to beproduced without application of heat to the ingredient mixture.Stability of the actives is therefore preserved, and a well-blended,soft texture is provided. Further, no water is used as an ingredient ofthe chews, thereby avoiding the need for use of costly pharmaceuticalgrade water, while reducing the opportunity for microbial growth or lossof potency by the active.

To these ends, the soft chews of the invention are manufactured usinglarge capacity horizontal mixers which spins the chew mixture intoparticulate form. The mixing action causes the ingredients in themixture to be cast away from the mixing vessel walls, crisscrossing thevessel to provide a uniformly blended mixture formed without applicationof heat. Because no cooling step is required, the time to produce chewsis shortened compared to cooking extrusion methods.

The highly blended mixture produced is placed into molds to formindividual dosage units and allowed to set without application of heat.Soft chews can be produced in any desired shape. Preferred mixing andmolding equipment utilized in the invention can provide individual softchews with consistently blended ingredients, stably provided actives andconsistent weights.

The soft chews of the invention are produced in palatable form withoutthe use of any non-food grade inactive ingredients (or, preferably, anyanimal origin inactive ingredients). The manufacturing processes maytherefore be performed without risk of potential cross-contamination ofother equipment in the facility with infectious agents or contaminantsderived from sources such as the animal-origin meat flavorings commonlyused in chewable medications for animals.

DETAILED DESCRIPTION OF THE INVENTION

A. Materials for use in Soft Chews of the Invention.

In general, soft chewable medications and treats include as inactiveingredients matter such as binding agents, vitamins, and colors toenhance the manufacturability, texture and appearance of the product.Those of ordinary skill in the art will be familiar with such inactiveingredients, which need not include water for use in the invention.

For use in the invention, no inactive ingredients of the soft chewshould be of less than food grade quality and may be of higher quality(e.g., USP or NF grade). In this context, “food grade” refers tomaterial that does not contain or impart chemicals or agents hazardousto health. Thus, a food grade flavoring, if of animal origin, will beone that has been prepared to substantially reduce or eliminate thepresence of infectious agents or contaminants therein; e.g., byprocesses such as pasteurization, pressurization or irradiation.

The latter process in particular can effectively eliminate infectiousagents such as E. coli O157:H7, Salmonella and Campylobacter from a widevariety of food and animal-derived substances, such as raw meatproducts, vegetables, grains and fruits. Preferably, however, soft chewsof the invention will not contain any animal origin ingredients, andmost preferably will not contain any animal origin flavorings. Allingredients should be pharmaceutically acceptable (e.g., food grade, USPor NF, as appropriate).

Flavorings are preferably present in soft chews of the invention thatare at least food grade in quality, and most preferably exclude animalorigin flavorings. Preferred non-animal origin flavorings are plantproteins, such as soy protein, to which edible artificial food-likeflavorings has been added (e.g., soy-derived bacon flavoring). Dependingon the target animal, other non-animal flavorings could include aniseoil, carob, peanuts, fruit flavors, sweeteners such as honey, sugar,maple syrup and fructose, herbs such as parsley, celery leaves,peppermint, spearmint, garlic, or combinations thereof.

A particularly preferred flavoring for use in the invention isProvestar™ 356, made by ABF Ingredients, Inc. It is a light tan,water-soluble powder that builds on the properties of yeast extracts andreaction flavors to provide a pleasant smoky, cured bacon flavor.Provesta 356 contains no animal derived ingredients.

For administration to horses and other grazing animals, as well as smallanimals such as rabbits, hamsters, gerbils, and guinea pigs, grains andseeds are especially appealing additional flavoring agents. The grainsmay be present in any form consistent with the production of the chewincluding flour, bran, cereal, fiber, whole grain and meal forms,including gluten meals, and may be rolled, crimped, ground, dehydratedor milled. Minerals may also be added as flavorings, such as salt andother spices. Preferably, the grain utilized is dehydrated, milled orflaked. Vegetables such as dehydrated carrots and seeds such assafflower seeds or milo seeds are especially appealing to small animalsand may be included.

Further, agents which enhance the manufacturability and texture of asoft chew may include softening agents, an anti-caking agent orlubricant, and a humectant or wetting agent. Illustrative examples oflubricants or anti-caking agents which may be used in the inventioninclude magnesium stearate, calcium stearate, solid polyethyleneglycols, sodium lauryl sulfate, or mixtures thereof. Magnesium stearateis particularly preferred for lubrication and as a component to aid insetting the soft chews after molding.

Humectants illustratively include glycerol and propylene glycol, andwetting agents include cetyl alcohol and glycerol monostearate. Glycerinis a preferred humectant useful in maintaining the softness of the softchew over the shelf life of the product. Glycerin is a clear, colorless,odorless, viscous, hygroscopic liquid.

Vegetable oils (such as corn, safflower, cottonseed, soybean and oliveoils) may also be utilized to lubricate the chew mixture and maintainits softness. Oil also aids in flavor palatability. A particularlypreferred oil is soybean oil.

Paraffin wax or polyethylene glycol 8000 (carbowax) will preferably beincluded in the soft chew mixture before molding at 1.0% to 3.0%. If waxis used, it is melted at 50° C. before being added to the soft chewmixture after mixing. After molding, the soft chews with the added waxwill set-up, usually over a period of 8 to 24 hours. The wax congealsquickly, softens the chew mixture, and prevents the soft chew units fromsticking together after molding.

Additional softening agents utilized are those which limit density andhardness of the soft chew product. Such agents may includepolysaccharides and fiber. A polysaccharide may be included in the formof a complex food such as a fruit, a plant starch such as potato ortapioca starch. Polysaccharide may also be provided separately, forexample, in the form of chondroitin sulfate or glucosamine HCl.

Fiber may be also provided as filler or as a bulking agent and toprovide or maintain porosity in the soft chew. Fibers used to this endmay be derived from fruits, grains, legumes, vegetables or seeds, orprovided in forms such as wood fiber, paper fiber or cellulose fibersuch as powdered cellulose fiber. A particularly preferred such bulkingagent for use in the invention is bran, such as oat bran.

Other bulking agents that may be utilized include any food gradematerial, including hydrocolloid thickeners and binders, such as gumarabic, pectins, modified starches, alginates, carrageenans, xanthangums, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, propylene glycolalginate, polyvinylpyrrolidone (PVP), carboxyvinyl polymers (such asCarbopol®), polyethylene oxide polymers (such as Polyox®), talc,dicalcium phosphate, and antacids.

Binders utilized in soft chews may be a sticky substance or a substancewhich becomes sticky in combination with other ingredients such aswater, but will preferably give the soft chew product a food-liketexture. In general, binders may include molasses, corn syrup, peanutbutter, food gum, a starch such as potato starch, tapioca starch or cornstarch, honey, maple syrup and sugars. Preferred binders for use in softchews of the invention are starches and powdered sweeteners.

A particularly preferred binder is Starch 1500, a pregelatinized starchmade by Colorcon Corporation. Pregelatinized starch is a starch that hasbeen chemically and/or mechanically modified to rupture all or part ofthe starch granules and so render the starch flowable. It contains 5% offree amylase, 15% of free amylopectin and 80% unmodified starch. Thesource is from corn.

Powdered sugar (sucrose) serves well as a sweetener as well as a binder.Sucrose is obtained from either sugar cane or sugar beets. Salt and/orother spices may be added as appropriate, with salt being especiallypreferred to enhance flavor.

A preservative such as potassium sorbate, sodium benzoate or calciumpropionate may be included in order to retard growth of microorganismsand fungi. Tenox 4 is a combination of BHA and BHT anti-oxidants, madeby Eastman Chemicals. It is a preferred and convenient preservationsystem.

Vitamins may be provided according to the nutritional requirements ofthe target animal, and may be provided as an element of oils utilized.Vitamins are also present in various oils that may be added as softeningagents; for example, canola oil, corn oil, soybean oil and vegetableoil.

Excipients that may be utilized include starches, cellulose, orderivatives or mixtures thereof, in amounts ranging, for example, fromabout 1 to about 60 percent (w/w), preferably from about 2 to about 50percent, more preferably from about 15 to 50 percent. For example, theexcipient may consist of sodium starch glycolate, pregelatinized cornstarch (Starch 1500), crospovidone (Polyplasdone XL™, InternationalSpecialty Products), and croscarmellose sodium (Ac-Di-Sol™, FMC Corp.),and derivatives thereof. Excipients may be used to create a triturationof an active. For example, to create a 10% trituration, 100 grams of theactive is combined with 900 grams of an excipient, such as a preferredexcipient, Starch 1500. The dry mixture is fluidized and is thenpreferably coated.

If a coating is to be provided (to help protect the stability of theactive and mask its taste), food grade coatings are preferred, such asan aqueous film coat from Colorcon Corporation sold as OPADRY™. OPADRYis a methylcellulose based product with a plasticizer and pigment. Sincethe coating is aqueous based, no special handling precautions arerequired during manufacture of the soft chew. However, afteradministration, the aqueous film coat will start to erode and/ordissolve within minutes when exposed to water or other liquids in thestomach. Therefore, disintegration and dissolution of the soft chewshould not be delayed after it is administered to the subject.

Any orally administrable active drug or other biologically activecompound may be provided in the soft chews of the invention. Those ofordinary skill in the human and/or veterinary pharmaceutical arts willbe entirely familiar with the identity of such actives which mayinclude, without limitation, antibiotics, analgesics, antivirals,antifungals, anthelmetics, endo- and ecto-parasticides, hormones and/orderivatives thereof, anti-inflammatories (including non-steroidalanti-inflammatories), steroids, behavior modifiers, vaccines, antacids,laxatives, anticonvulsants, sedatives, tranquilizers, antitussives,antihistamines, decongestants, expectorants, appetite stimulants andsuppressants, minerals and vitamins.

The amounts of each of the components in the final product may be variedconsiderably, depending upon the nature of the drug, the weight andcondition of the subject treated, and the unit dosage desired. Those ofordinary skill in the art will be able to adjust dosage amounts forparticular actives in the soft chews in light of the teachings of thisdisclosure. Generally, however, the active may be provided by range inweight based on the total weight of the composition from about 0.001% to75% (w/w), more preferably 0.095% to 40%, and most preferably not inexcess of 50%. For example, for administration of an anthelmetic todogs, such as ivermectin for treatment of heartworms (see, Example 1)triturated with starch could be added to comprise 31.2% of the foregoingmixture.

The formula described for the exemplary product may be easily modifiedfor delivery of actives to other species. For example, equine soft chewsmay be based on the same basic formula, substituting molasses powder,oat bran and apple for the bacon. Flavorings particularly appealing tocats include artificial soy based compounds with a fish-like flavor.Human recipients may prefer sweeter flavorings, such as sugars ormolasses.

The soft chews of the invention may be packaged individually foradministration and stable storage. Examples of suitable packagingmaterials include HDPE bottles or foil/foil packaging.

B. Processes for Manufacturing Soft Chews of the Invention

Active and inactive ingredients for a soft chew of the invention areadded to a mixing vessel of a horizontal mixer capable of blending thematerial and casting it against the side of the mixing vessels. Thisaction permits the ingredients to be well and consistently blendedwithout application of heat or addition of pharmaceutical grade water tothe mixture.

Horizontal mixers generally comprise a mixing chamber, an elongated,horizontal mixing shaft which rotates, and a plurality of mixing toolswhich depend generally perpendicularly from the horizontal shaft torotate around the inside of the chamber. (See, e.g., U.S. Pat. No.5,735,603, the disclosure of which is incorporated herein by thisreference). The mixing tools are configured and dimensioned as requiredfor the mixing process to follow the shape of the chamber walls asrotated for proper mixing of all of material present. Some such mixingchambers are cylindrically shaped, while others are trough-shaped, suchas mixers which are commonly referred to in the art as double-arm mixersor ribbon mixers.

In general, a horizontal mixer will have a horizontal mixing shaftextending out of the chamber at both ends. In a motorized mixer, at oneend of the shaft, referred to as the drive end, the shaft is operablycoupled to a drive motor for rotating the shaft. At the drive end, theshaft is typically coupled through a bearing structure located betweenthe drive motor and the chamber. The bearing structure provides supportof the shaft drive end and also ensures smooth rotation. A separate sealstructure is often provided further in along the length of the shaft toseal it against leakage of material into and out of the mixing chamber.

A particularly preferred mixer for use in the invention used is a ploughtype ribbon mixer with optional agitating blades, sold under the FXMSERIES™ trademark by Littleford Day Corporation. A 200 kg capacityblender can be used for commercial scale production, and is capable ofproducing as little as 50 kg of chew mixture for research scale work. Noheat is applied during mixing, and the blended product produced has aconsistent weight, ingredient distribution and texture from batch tobatch.

Preferably, dry ingredients of the chew mixture are blended first, thenliquid ingredients (e.g., humectants and softening agents) are added andblended therein to form a thoroughly blended mixture. After blending,the chew mixture is discharged from a port through the blender into asuitable container for processing into individual dosage units with aforming machine.

A variety of forming equipment may be utilized in the invention, butthose particularly preferred for use are molding machines developed foruse in producing molded food products, such as pre-formed hamburgerpatties and chicken nuggets. For example, the molding machines disclosedin U.S. Pat. Nos. 3,486,186; 3,887,964; 3,952,478; 4,054,967; 4,097,961;4,182,003; 4,334,339; 4,338,702; 4,343,068; 4,356,595; 4,372,008;4,535,505; 4,597,135; 4,608,731; 4,622,717; 4,697,308; 4,768,941;4,780,931; 4,818,446; 4,821,376; 4,872,241; 4,975,039; 4,996,743;5,021,025; 5,022,888; 5,655,436; and 5,980,228 (the disclosures of whichare incorporated herein) are representative of forming equipment thatmay be utilized in the invention.

Preferred forming equipment for use in the invention includes the FormaxF6™ molding machine made by the Formax Corporation. The F6 machine hasthe capabilities of 60 stokes per minute. A square forming die of 6″ by6″ can be used to form approximately 16 chunk-like soft chew units perstroke, each unit weighing 4 grams and being approximately ⅝″ by ⅝″ insize. Dies for production of other shapes (e.g., bone shaped chews) mayalso be utilized.

In such a machine, a rotary valve opens to cause the chew mixture toflow through fill slots beneath into a first set of mold cavities. Amold plate is advanced, forcing the chew mixture into a second set ofcavities, then the mold plate is retracted so the cycle can begin again.The molding mechanism is hydraulic, and works by light pressure on themolding plate, without application of heat.

A knockout mechanism is provided with cups that align with the cavitiesto eject molded mixture. from all the mold plate cavitiessimultaneously. For molding soft chews of the invention, such a machinecould produce an output per hour of approximately 57,600 units, assuminguse of a blender mixture yielding 50,000 units per sub batch. Each batchof chews may be packaged in bulk or, preferably, each chew is thenindividually packaged for storage.

The invention having been fully described, its practice is illustratedby the examples provided below. Standard abbreviations and measurementsapply throughout the examples unless a contrary definition is given. Theexamples do not limit the scope of the invention, which is definedentirely by the appended claims.

EXAMPLE 1 Ivermectin Soft Chew for Treatment of Heartworms

An example of a soft chew suitable for delivery of an active is setforth in Formula 1 below. Formula 1: Concentration % w/w Ingredient47.90 Starch 1500, USP 1.0 Powdered Sugar, USP 2.0 Oat Bran, Food Grade15.0 Bacon Flavor (Provesta ™ 356), Food Grade 2.0 Polyethylene glycol8000 20.0 Glycerin, USP 7.0 Vegetable Oil (soybean), USP 0.1 Tenox 4,Food Grade 1.0 Magnesium Stearate, USP 1.0 Yeast Flavoring 3.0Croscarmellose, sodium N.F. 0.001 FD&C Carmine Dye

EXAMPLE 2 Method for Coating Active Ingredients of Soft Chews of theInvention

The active (ivermectin) was milled and screened through a 20 meshscreen. A 10% trituration was made by dry blending 100 grams ofivermectin and 900 grams of Starch 1500 for 3 to 5 minutes. Theresultant trituration was fluidized in a fluidized bed column and a foodgrade coating (OPADRY™) was applied using a Wurster coater, a top sprayfluidized coater, or other suitable device.

EXAMPLE 3 Exemplary Method of Manufacture for Soft Chews of theInvention

All dry ingredients listed in Examples 1 and 2 except the oat bran weresifted through a 20 mesh screen, then placed with the bran into themixing vessel of a horizontal mixing blender and mixed for 5 minutes.The glycerin was added slowly followed by the slow addition of thevegetable oil and Tenox 4 which had been added to the oil. The productwas mixed for 3 minutes. The PEG 8000 was melted then added relativelyquickly to the chew mixture, which was then mixed for an additionalminute. The mixture resembled a “cookie dough-like” appearance.

The mixture was formed into individual chunks using a Formax F6™ moldingmachine with dies for production of chunk-like shapes, and packaged forstorage.

The invention having been fully described, its scope is defined by theclaims appended hereto.

1. A process for manufacturing a soft chewable medication vehicle fordelivery of a pharmaceutically active ingredient, the method comprising:(a) providing the active ingredient and dry inactive ingredients of themedication vehicle to a mixing chamber of a mixer, wherein: (i) thechamber is generally horizontally disposed and has a space thereindefined by walls to receive material to be mixed; (ii) a rotatablemixing shaft extends longitudinally through the chamber space; and,(iii) a drive apparatus is operably coupled to the mixing shaft forrotating the shaft, (b) blending the dry active and inactive ingredientsin the mixing chamber by causing the mixing shaft to be rotated to castthe ingredients in a pattern away from and between the walls of themixing chamber space until a dry mixture is formed; (c) adding asoftening agent to the dry mixture and blending it therein to form asoft chewable mixture; and, (d) forming the soft chewable mixture intoindividual masses, wherein the masses are of consistent weight, whereinfurther no heat is applied to the dry or blended chewable mixture duringany of the mixing or forming steps.
 2. The process according to claim 1,further comprising the step of preparing a trituration of the activeingredient with an excipient before the active ingredient is added tothe mixing vessel in step (a).
 3. The process according to claim 1,further comprising the step (c)′ of adding melted paraffin wax to thesoft chewable mixture and blending it therein.
 4. The process accordingto claim 1 or claim 2, further comprising the step (d)′ of coating theactive ingredient with a food grade coating before the active ingredientis added to the mixing vessel in step (a).
 5. The process according toclaim 1, further comprising step (e) wherein the individual masses areplaced into a pharmaceutically acceptable container.
 6. A medicationvehicle comprising of a pharmaceutically acceptable active ingredient ina soft chewable mass, wherein the medication is produced according tothe process of claim
 1. 7. The medication vehicle according to claim 6,further comprising inactive ingredients, wherein all of the inactiveingredients are of food grade quality.
 8. The medication vehicleaccording to claim 7, wherein the inactive ingredients are irradiated orpasteurized.
 9. The medication vehicle according to claim 6, furthercomprising inactive ingredients, wherein none of the inactiveingredients are of animal origin.
 10. The medication vehicle accordingto claim 7, wherein the inactive ingredients include flavorings of foodgrade quality.
 11. The medication vehicle according to claim 9, whereinthe inactive ingredients include flavorings of non-animal origin. 12.The medication vehicle according to claim 11, wherein the flavoring is asoy protein product.
 13. The medication vehicle according to claim 12,wherein the flavoring is an artificially bacon flavored soy proteinproduct.
 14. The medication vehicle according to claim 6, furthercomprising a lubricant, a humectant, and a bulking agent.
 15. Themedication vehicle according to claim 6, wherein the pharmaceuticallyactive ingredient is prepared in a trituration with an excipient. 16.The medication vehicle according to claim 14, wherein the softeningagent comprises an oil.
 17. The medication vehicle according to claim14, wherein the softening agent comprises wax.
 18. The medicationvehicle according to claim 6, wherein the pharmaceutically active agentis coated.
 19. The medication vehicle according to claim 6, furthercomprising a preservative.
 20. The medication vehicle according to claim14, wherein the softening agent comprises an oil and a wax, thehumectant comprises glycerin, and the lubricant comprises a stearate.21. The medication according to claim 20, wherein the pharmaceuticallyactive ingredient is selected from the group of ingredients consistingof anthelmetics, analgesics, antibiotics, antivirals,anti-inflammatories, endo-parasiticides, ecto-parasiticides andantifungals.
 22. The medication according to claim 21, wherein thepharmaceutically active ingredient is an anthelmetic.
 23. The medicationaccording to claim 22, having the ingredients of Formula 1 and an activeingredient.